Tailored apoptotic vesicles promote bone regeneration by releasing the osteoinductive brake

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-04-16 DOI:10.1038/s41368-024-00293-0
Yawen Cheng, Yuan Zhu, Yaoshan Liu, Xuenan Liu, Yanan Ding, Deli Li, Xiao Zhang, Yunsong Liu
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Abstract

Accumulating evidence has demonstrated that apoptotic vesicles (apoVs) derived from mesenchymal stem cells (MSCs; MSC-apoVs) are vital for bone regeneration, and possess superior capabilities compared to MSCs and other extracellular vesicles derived from MSCs (such as exosomes). The osteoinductive effect of MSC-apoVs is attributed to their diverse contents, especially enriched proteins or microRNAs (miRNAs). To optimize their osteoinduction activity, it is necessary to determine the unique cargo profiles of MSC-apoVs. We previously established the protein landscape and identified proteins specific to MSC-apoVs. However, the features and functions of miRNAs enriched in MSC-apoVs are unclear. In this study, we compared MSCs, MSC-apoVs, and MSC-exosomes from two types of MSC. We generated a map of miRNAs specific to MSC-apoVs and identified seven miRNAs specifically enriched in MSC-apoVs compared to MSCs and MSC-exosomes, which we classified as apoV-specific miRNAs. Among these seven specific miRNAs, hsa-miR-4485-3p was the most abundant and stable. Next, we explored its function in apoV-mediated osteoinduction. Unexpectedly, hsa-miR-4485-3p enriched in MSC-apoVs inhibited osteogenesis and promoted adipogenesis by targeting the AKT pathway. Tailored apoVs with downregulated hsa-miR-4485-3p exhibited a greater effect on bone regeneration than control apoVs. Like releasing the brake, we acquired more powerful osteoinductive apoVs. In summary, we identified the miRNA cargos, including miRNAs specific to MSC-apoVs, and generated tailored apoVs with high osteoinduction activity, which is promising in apoV-based therapies for bone regeneration.

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定制的凋亡囊泡通过释放骨诱导制动器促进骨再生
越来越多的证据表明,间充质干细胞(间充质干细胞;MSC-apoVs)产生的凋亡囊泡(apoVs)对骨再生至关重要,与间充质干细胞和间充质干细胞产生的其他细胞外囊泡(如外泌体)相比,间充质干细胞-apoVs具有更强的能力。间充质干细胞无泡囊泡的骨诱导作用归因于其丰富的内容物,尤其是富含蛋白质或微量核糖核酸(miRNA)。为了优化它们的骨诱导活性,有必要确定间充质干细胞蛋白apoVs独特的载货特征。我们以前曾建立了间充质干细胞-apoVs的蛋白质图谱,并鉴定了间充质干细胞-apoVs的特异性蛋白质。然而,MSC-apoVs中富集的miRNA的特征和功能尚不清楚。在这项研究中,我们比较了来自两种间充质干细胞的间充质干细胞、间充质干细胞apoVs和间充质干细胞外泌体。我们绘制了一张MSC-apoVs特异性miRNA图谱,并发现了7种与间充质干细胞和间充质干细胞外小体相比在MSC-apoVs中特异性富集的miRNA,我们把它们归类为载脂蛋白V特异性miRNA。在这七种特异性 miRNA 中,hsa-miR-4485-3p 的含量最高且最稳定。接下来,我们探讨了它在载脂蛋白V介导的骨诱导中的功能。意想不到的是,在间充质干细胞-apoVs中富集的hsa-miR-4485-3p通过靶向AKT通路抑制骨生成并促进脂肪生成。与对照apoVs相比,下调了hsa-miR-4485-3p的定制apoVs对骨再生的影响更大。就像松开刹车一样,我们获得了更强大的骨诱导载脂蛋白。总之,我们鉴定了miRNA cargos,包括间充质干细胞载脂蛋白的特异性miRNA,并生成了具有高骨诱导活性的定制载脂蛋白,这在基于载脂蛋白的骨再生疗法中大有可为。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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